Alcoholism is a serious and prevalent health problem whose etiology/pathogenesis remains unclear. To understand alcoholism, it is essential to have animal models, such as the P and NP rats which were developed at Indiana University. Recent studies have shown that a lower content of monoamines exists in several brain regions of the P as compared with the NP rats. Our preliminary studies have also shown that there are alterations of 5-HT and GABAergic neurons in the hippocampus and nucleus accumbens, respectively, in the P rats. Many lines of evidence suggest that DA, GABA and, in particular, 5-HT systems may be involved in alcohol-seeking behavior. We, therefore, propose to study these three systems in the following major brain areas: nucleus accumbens, hippocampus, frontal cortex, and basal ganglia, areas which may be functionally related to the rewarding features of drinking, sensory perception, anxiety, and sensorimotor regulation, to reveal neuroanatomical substrates for alcoholic behavior. We aim to examine the monoaminergic systems of P and NP rats at three levels--terminals, pathways, and synapses. Specifically, we will (1) use immunocytochemistry and densitometry to study whether/how 5-HT, DA and GABA terminals are altered in the above-mentioned areas in P and NP rats; (2) apply track-tracing, immunocytochemistry, and molecular biology methods to evaluate the alteration in neuronal pathway, transmitter level, and neuronal population of 5-HT, DA,and GABA neurons in the raphe-accumbens (5-HT), ventral tegmentum-accumbens (DA) and accumbens (local GABA) which are closely related to brain reward; (3) reveal the microcircuitry of GABA/5-HT, GABA/DA, and 5-HT/DA synaptic connections in the nucleus accumbens. Increasing evidence suggests that neuropharmacological manipulations to increase 5-HT transmission in the brain reduces alcohol drinking in the rodent. We propose to further extend this hypothesis utilizing 5-HT neuronal transplantation to test whether replenishing 5-HT neurons in 5-HT-deficient brain regions will ameliorate the drinking behavior in P rats.